Despite progress in prevention and treatment, breast cancer remains the second leading cause of cancer- related death in women. As the field seeks new approaches, especially for estrogen receptor-negative disease, strategies to modulate chronic tumor inflammation and reverse immune suppression show significant promise. Such therapies require identification of effective molecular targets in the tumor microenvironment. Cyclooxygenase-2 (COX-2) is an established and clinically effective target in cancer prevention. However, the proven anti-tumor benefit of systemic COX-2 inhibition, which results from reduced of COX-2-prostaglandin E2 in tumors, is accompanied by unwanted loss of endothelial COX-2-prostacyclin, elevating thrombotic risk. We asked if the established mechanistic distinctions between the anti-tumor and pro-thrombotic effects of systemic COX-2 inhibition provide novel molecular targets for non-systemic COX-2 inhibition to suppress tumors without increasing thrombosis. In recent studies, proposed originally in the 1st submission of this R03, we determined that selective deletion of macrophage cyclooxygenase-2 (COX-2) was sufficient to robustly reduce mammary tumorigenesis by suppressing infiltrating cytotoxic T-lymphocytes (Chen et al., 2013 resubmitted to Cancer Research). Now, in this R03 resubmission, we propose to translate these exciting new findings to an innovative nanotherapeutic approach to suppress mammary tumors without elevating thrombotic risk by selective inhibition of macrophage COX-2. High-density lipoprotein (HDL) is a biodegradable and biocompatible nanoparticle that naturally targets macrophages. In Specific Aim 1 we will use reconstituted (r) HDL nanoparticles to selectively deliver a COX-2 inhibitor to macrophages. We will establish selective inhibition of macrophage COX-2 with sustained anti- thrombotic endothelial COX-2 activity. In Specific Aim 2 we will establish the efficacy of the nanotherapy, compared to systemic COX-2 inhibition, to delay mammary tumor onset, reduce disease burden, slow tumor growth and modify the tumor microenvironment, in two models of her2/neu-induced disease. Success in this R03 is highly likely - the target, macrophage COX-2, is validated in mammary tumor models, the approach, rHDL macrophage targeting, is established, and we have the necessary models, reagents and expertise. This resubmission is the beginning of a new cross-disciplinary collaboration between UPenn's Institute for Translation Medicine and Therapeutics and Mt Sinai School of Medicine's Nanomedicine Program that lays the foundation for future pre-clinical and clinical therapeutic and safety studies of rHDL COX-2 inhibitor nanotherapy to suppress breast and other cancers. Our overarching goal is a safe and effective approach to realize the promise of COX-2 inhibition in cancer prevention and treatment without cardiovascular hazard. Development of such a targeted nanotherapeutic may have a profound impact on public health and cancer prevention and therapy especially in high-risk individuals and families.